Method and device

ABSTRACT

The invention relates to a method and device for treating or preventing or suppressing a disease or condition in a non-human animal. The method comprises the steps of providing a single delivery device containing two components for sequential delivery from the delivery device. A first component is delivered from the single delivery device into a teat canal of a non-human animal and subsequently the second component is delivered from the single delivery device into the teat canal. The components are delivered without substantial mixing of the components.

INTRODUCTION

The invention relates to a method and device for administering twocomponents into the teat canal of a non-human animal.

Bovine mastitis is a severe, potentially fatal, inflammatory disease ofthe udder, caused by a broad range of infectious organisms, but mostnotably by various Gram positive bacteria of the genera Staphylococcusand Streptococcus and the Gram negative species, Escherichia coli. Theinfection usually enters the udder via the teat or streak canal.Mastitis is treated by a variety of antibiotic cerates, infused into theudder via the teat or streak canal. In severe cases, high doses ofantibiotic are also given by injection. A high proportion of mastiticinfections are contracted during the “dry” period, which precedescalving. The infection may later become clinically significant eitherduring the dry period, or after calving when lactation has resumed.

It is known to treat mastitis using a twin injector pack, one injectorcontaining an anti-bacterial formulation and a second injectorcontaining a seal or barrier formulation. The anti-bacterial formulationis delivered first to the teat canal followed by delivery of the sealformulation forming a physical barrier in the teat canal against theentry of bacteria into the udder. These twin injector packs are soldunder the name Teat Seal™. WO94/13261 and WO95/31180 describe the twininjectors in detail and are hereby incorporated by reference.

While the twin injector system provides an effective method to reducethe incidence of clinical mastitis administration of the injectors canbe time consuming, doubles the risk of introducing extraneousenvironmental bacteria and doubles the risk of causing damage to theepithelium of the streak canal. The use of two injectors also increasesthe cost of treatment and creates additional non-degradable waste.

There is a need for an improved method and device for preventingintrammary disorders which will overcome at least some of theseproblems.

STATEMENTS OF INVENTION

According to the invention there is provided a method for treating orpreventing or suppressing a disease or condition in a non-human animalcomprising the steps of:

-   -   providing a single delivery device containing two components for        sequential delivery from the delivery device;    -   delivering a first component from the single delivery device        into a teat canal of a non-human animal; and    -   subsequently delivering the second component from the single        delivery device into the teat canal without substantial mixing        of the components.

In one embodiment the delivery device comprises an injector devicecontaining the two components, the components being separated by abarrier and the method comprises the steps of:

-   -   delivering the first component from the injector device;    -   at least partially releasing the barrier; and    -   subsequently delivering the second component o the injector        device.

In another embodiment the disease or condition is mastitis and themethod of the invention is for treating or preventing a mastitis-causingmicro-organism.

In a further embodiment the second component comprises a seal.

According to a further aspect the invention provides a method fortreating, preventing or suppressing mastitis or a mastitis causingmicro-organism comprising the steps of sequentially delivering from asingle delivery device an antimicrobial formulation and a sealformulation into the teat canal of a non-human animal wherein theantimicrobial formulation and the seal formulation are delivered intothe teat canal without substantial mixing of the formulations prior todelivery into the teat canal.

In one embodiment the seal formulation comprises a non-toxic heavy metalsalt.

In another embodiment the seal formulation comprises greater than 40% byweight of the heavy metal salt.

In a further embodiment the seal formulation comprises between 50% and75% by weight of the heavy metal salt.

In one embodiment the seal formulation comprises approximately 65% byweight of the heavy metal salt.

In another embodiment the heavy metal is bismuth.

In a further embodiment the salt is a sub-nitrate salt.

In one embodiment the seal formulation comprises a gel base.

In another embodiment the gel base is a gel based on aluminum stearate,

In a further embodiment the gel base includes liquid paraffin as avehicle.

In one embodiment the first component comprises an antimicrobial.

In another embodiment the antimicrobial is selected from any one or moreof betalactam antibiotics, polymyxins, glycopeptides, aminoglycosides,lincosamides, macrolides, pleuromutilins, “fenicols” such aschloramphenicol and florfenicol, tetracylcines, sulphonamides andpotentiated sulphonamides such as mixtures of trimethoprim and one ormore sulphonamide, quinolones and fluoroquinolones, ionophores,courmarins such as novobiocin, natural or synthetic peptides,aminoglycosides, antimicrobial peptides or antimicrobials, lantibiotics,or other products of bacteria and other micro-organisms.

In a further embodiment the betalactam is selected from any one or moreof penicillin, modified penicillin such as cloxacillin, amoxycillin,ampicillin, cephalosporins or beta lactam antibiotics potentiated bybeta lactamase inhibitors such as clavulanic acid.

In one embodiment the aminoglycoside is selected from any one or more ofstreptomycin, dihydrostreptomycin, neomycin, gentamycin, framycetin,aparamycin or kanamycin.

In another embodiment the antimicrobial is selected from any one or moreof macrolide, lincosamide or pleuromutilin, erythromycin, spiramycin,tylosin, spiramycin, tilmicosin, lincomycin, spectinomysin, pirlimycinor tiamulin.

In a further embodiment the antimicrobial is selected from any one ormore of potentiated sulphonamide mixtures, trimethoprim plussulphadiazine, sulphadimidine, sulphadoxine, sulphadimethoxine or othersulphonamide, oxytetracycline, minocycline or doxyclycline,fluoroquinolones, enrofloxacin, ciprofloxacin, norfloxacin,danofloxacin, difloxacin or marbofloxacin.

In one embodiment the first component comprises an anti-inflammatory.

In another embodiment the anti-inflammatory is selected from any one ormore of steroids such as prednisolone, betamethazone, dexarnethazone,phenylbutazone, or non-steroids such as flunixin, ketoprofen, carprofen,vedaprofen, meloxicam, tepoxalin, eltenac, nimesulide or tolfenamicacid.

According to further aspect of the invention there is provided aninjector device for delivery of components into the teat canal of anon-human animal comprising:

-   -   a barrel for containing a first component,    -   an outlet nozzle at one end of the barrel,    -   an internal receptacle for containing a second component,    -   a barrier for separating a first component and a second        component, and    -   a delivery means for delivery of a first component from the        barrel and sequential delivery of a second component from the        internal receptacle through the outlet nozzle.

In one embodiment the barrier is normally closed.

In another embodiment the barrier is releasable for delivery of thesecond component.

In a further embodiment the barrier is defined by at least a portion ofthe internal receptacle.

In one embodiment the barrier comprises one or more passageways.

In another embodiment the one or more passageways are opened when thebarrier is released for delivery of the second component through saidone or more passageways.

In a further embodiment the device comprises an activator for releasingthe barrier.

In one embodiment the activator comprises a mechanical activator means.

In another embodiment the activator comprises at least one projectingmember.

In a further embodiment the activator is located in the barrel.

In one embodiment the activator is located adjacent to the outletnozzle.

In another embodiment the activator comprises one or more passageways.

In a further embodiment the activator is configured for engagement withthe internal receptacle to provide a direct passageway for delivery ofthe second component from the internal receptacle into the outletnozzle.

In one embodiment the delivery means comprises a plunger for the barrel

In another embodiment the barrier is released by the delivery means.

In a further embodiment the internal receptacle comprises an innerbarrel located within an outer barrel defined by the barrel of theinjector.

In one embodiment the inner barrel is a close fit within the outerbarrel.

In another embodiment the delivery means comprises the inner barrel.

In a further embodiment the inner barrel defines a plunger for the outerbarrel.

In one embodiment the delivery means comprises a plunger for the innerbarrel.

In another embodiment the inner barrel comprises engagement means forengagement with the outer barrel on assembly.

In a further embodiment the engagement means comprises an external seal.

In one embodiment the outer barrel comprises engagement means forengagement with the inner barrel.

In another embodiment the outer barrel comprises a locking ring forengagement with the inner barrel.

In a further embodiment the inner barrel comprises engagement means forengagement with the plunger.

In one embodiment the inner barrel comprises a locking ring forengagement with the plunger.

In another embodiment the receptacle comprises a bag.

In a further embodiment the receptacle comprises a capsule.

In one embodiment the receptacle is attached to or forms an integralpart of the delivery means.

In another embodiment the activator comprises a rupturing means for atleast partially releasing the barrier.

In a further embodiment the rupturing means comprises a mechanicalrupture member.

In one embodiment the rupture member comprises at least one blade.

In another embodiment the rupture member comprises at least one tooth.

In a further embodiment the rupture member is located in the barrel.

In one embodiment the rupture member is located adjacent to the outletnozzle.

In another embodiment the barrel contains a first component.

In a further embodiment the first component comprises an antimicrobialformulation.

In one embodiment the internal receptacle contains a second component.

In another embodiment the second component comprises a seal formulation.

In a further embodiment a first component is delivered from the barreland a second component is subsequently delivered from the internalreceptacle without substantial mixing of the components.

In one embodiment the seal formulation may comprise the seal formulationas described above.

In another embodiment the antimicrobial formulation may comprise theantimicrobial formulation as described above.

BRIEF DESCRIPTION OF DRAWINGS

The invention will be more clearly understood from the followingdescription thereof given by way of example only with reference to theaccompanying drawings, in which:

FIG. 1 is a schematic cross sectional view of an injector deviceaccording to the invention;

FIG. 2 is a cross sectional view of an internal barrel of the device;

FIG. 3 is a cross sectional view of the internal barrel of FIG. 2 with aseal component in place;

FIG. 4 is a cross sectional view of the internal barrel of FIG. 3 with aplunger inserted;

FIG. 5 is a cross sectional view of an external barrel of the device;

FIG. 6 is a cross sectional view of the external barrel of FIG. 5 withan antimicrobial component in place;

FIG. 7 is a cross sectional view of the assembled injector device;

FIGS. 8(a) to 8(c) are cross sectional views of the injector device, inuse;

FIG. 9 is a cross sectional view of another injector of the invention;

FIG. 9(a) is an enlarged view of portion of the injector in FIG. 9;

FIGS. 10 to 12 are cross sectional views of a further injector deviceaccording to the invention in different configurations of use;

FIG. 13 is a top plan view of the device of FIG. 9;

FIGS. 14(a) to 14(c) are cross sectional views of a further injectordevice according to the invention in different configurations of use;

FIG. 15 is an exploded broken out view of components of the injector ofFIG. 14;

FIG. 16(a) is a detailed cross sectional view of a portion of theinjector of FIG. 14, and FIGS. 16(b) and 16(c) are detailed perspectiveviews of a portion of the device in the configurations of FIGS. 14(b)and (c) respectively;

FIG. 17 is a schematic cross sectional view of an injector deviceaccording to a further embodiment of the invention;

FIGS. 18(a) to 18(d) are cross sectional views of the device of FIG. 17,in use;

FIG. 19 is a schematic cross sectional view of another injector deviceaccording to the invention; and

FIGS. 20(a) to 20(c) are cross sectional views of the injector device ofFIG. 19, in use.

DETAILED DESCRIPTION

The invention provides an injector device that allows for the sequentialdelivery of two incompatible components such as an antimicrobialformulation and a seal formulation into the teat canal of a non-humananimal. The seal formulation and antimicrobial formulation are containedseparately within a single injector device. This enables the product tobe stored without affecting the stability of either component. Thedevice also provides for the delivery of the antimicrobial formulationahead of the seal formulation which effectively forms a physical barrierin the teat canal preventing any further entry into the teat canal. Theseal formulation also prevents the possibility of the antimicrobialphase leaking or being expressed from the teat by gravitational orhydrostatic forces.

The seal formulation may comprise a viscous oil-based cerate containinga high proportion of a heavy metal salt, bismuth subnitrate. The productTeat Seal (trade mark of Cross Vetpharm Group) is described in detail inWO98/26759 and comprises a non-toxic heavy metal salt in a gel base. Thebase is a gel based on aluminum stearate. The gel preferably includes avehicle such as liquid paraffin. The gel may also comprise apolyethylene gel. The gel may be based on low density polyethylene or onhigh density polyethylene. Preferably, the heavy metal salt is presentin an amount of greater than 40%, preferably between 50% and 75% byweight, most preferably approximately 65% by weight.

The seal formulation prevents infection entering the udder via the teator streak canal through a combination of its viscosity, density andadhesiveness.

The antimicrobial or anti-inflammatory formulation may be selected fromany one or more of a wide variety of compounds that are known to beeffective for the treatment, prevention and elimination of mastitis andmastitis-causing organisms, including inter alia gram positive and gramnegative bacteria, yeasts, fungi and rickettsias. The antimicrobial oranti-inflammatory materials may include inter alia beta lactamantibiotics such as penicillins and cephalosporins, beta lactamantibiotics potentiated by beta lactamase inhibitors such as clavulanicacid, polymyxins, glycopeptides, aminoglycosides, lincosamides,macrolides, pleuromutilins, “fenicols” such as chloramphenicol andflorfenicol, tetracyclines, sulphonamides and potentiated sulphonamidessuch as mixtures of trimethoprim and one or more sulphonamide,quinolones and fluoroquinolones, ionophores, coumarins such asnovobiocin, natural or synthetic peptides, lantibiotics, and otherantimicrobial products of bacteria and other micro-organisms.

Other antimicrobials may be selected from any one or more of macrolide,lincosamide or pleuromutilin, erythromycin, spiramycin, tylosin,spiramycin, tilmicosin, lincomycin, spectinomysin, pirlimycin, tiamulin,potentiated sulphonamide mixtures, trimethoprim plus sulphadiazine,sulphadimidine, sulphadoxine, sulphadimethoxine or other sulphonamide,oxytetracycline, minocycline or doxyclycline, fluoroquinolones,enrofloxacin, ciprofloxacin, norfloxacin, danofloxacin, difloxacin ormarbofloxacin.

The second component may be selected from any one or more ofanti-inflammatory compounds, steroids such as prednisolone,betamethazone, dexamethasone, phenylbutazone, or non-steroids such asflunixin, ketoprofen, carprofen, vedaprofen, meloxicam, tepoxalin,eltenac, nimesulide or tolfenamic acid.

Other antimicrobial or anti-inflammatory compounds used in the treatmentof intramammary infections in non-human animals may also be used.

These antimicrobial or anti-inflammatory materials may be formulatedeither singly or in combinations of two or more compounds as liquids,cerates, solutions, suspensions emulsions or flowable powders in water,oil (of animal, vegetable, mineral or other origin) or other organicvehicles. Other excipients such as solubilising, suspending oremulsifying agents, viscosity modifiers, surfactants, encapsulatingagents and other means to adjust the rate at which the compound(s) isreleased from the formulation, buffers and such agents to maintain thepH of the formulation, anti-inflammatory agents such as varioussteroidal and non-steroidal compounds commonly used for this purpose,and various preservative agents commonly used in pharmaceuticalpreparations.

Referring to the drawings an initially to FIGS. 1 to 8 there isillustrated an injector device 1 according to the invention. Theinjector device 1 in this case comprises an inner barrel 2 and an outerbarrel 3. The outer barrel 3 has a nozzle 4. The inner barrel 2 containsa first component comprising a seal 9. The barrel 2 has a barrier ormembrane 5 at its distal end. A plunger 6 is inserted into proximal endof the inner barrel 2 above the seal component 9. An antimicrobial oranti-inflammatory component 10 is contained within the outer barrel 3below the inner barrel 2. In use, the nozzle 4 is inserted into a teatcanal 20 of a non-human animal such as a cow.

The inner barrel 2 is pushed through the outer barrel 3 by the plunger 6to expel the antimicrobial or anti-inflammatory component 10 (FIG.8(a)). When the antimicrobial or anti-inflammatory component 10 has beenexpelled (FIG. 8(b)) the plunger 6 on the inner barrel 2 is furtherdepressed to expel the seal 9 from the inner barrel 2. The pressure ofthe plunger 6 may be sufficient to release or rupture thebarrier/membrane 5 on the inner barrel 2 allowing the seal 9 to beexpelled from the injector device through the nozzle 4 and into the teatcanal (FIG. 8(c)). Rupturing means such as teeth 30 situated within theouter barrel 3 adjacent to the outlet nozzle 4, may be used to releaseor rupture or open the barrier/membrane 5.

Referring to FIGS. 9 and 9(a) there is illustrated another injectorwhich is similar to the injector of FIGS. 1 to 8 and like parts areassigned the same reference numerals. The injector device I comprises aninner barrel 2 and an outer barrel 3. The outer barrel 3 has a nozzle 4.In this case the barrier is released by an activator defined by a numberof spikes 50 projecting upwardly to different lengths. Themembrane/barrier has a portion 51 which is knocked-out by the spikes 50to allow ejection of the seal component. The distal end of the innerbarrel 2 has a seal or frill 53 which seals with the inner wall of theouter barrel 3.

Referring to FIGS. 10 to 13 there is illustrated a further injectorwhich is again similar to that of FIGS. 1 to 8 and like parts areassigned the same reference numerals. The injector device 1 comprises aninner barrel 2 and an outer barrel 3. The outer barrel 3 has a nozzle 4.In this case the barrier comprises a valve 60 at the distal end of theinner barrel 2. An activator 61 projects upwardly from the lower wall ofthe outer barrel. In use, when the inner barrel 2 is in theconfiguration of FIG. 11 the valve 60 is lifted by engagement with theactivator 61 and allows the seal component 9 in the inner barrel 2 topass through the injector nozzle 4.

When the plunger 6 is pushed down, the inner barrel 2 also travels downthrough the outer barrel 3. The outside of the inner barrel 2 is a closefit in the outer barrel 3 so that the inner barrel 2 itself acts as adelivery device or plunger for delivery of the first component from theouter barrel 3 through the nozzle 4.

Referring to FIGS. 14 to 16 there is illustrated another injector whichis again similar to the injector of FIGS. 1 to 13 and like parts areassigned the same reference numerals. The injector device comprises aninner barrel 2 and an outer barrel 3. The outer barrel 3 has a nozzle 4.The inner barrel 2 contains a seal component 9. A plunger 6 is insertedinto proximal end of the inner barrel 2 above the seal component 9.Antimicrobial 10 is contained within the outer barrel 3. In use, thenozzle 4 is inserted into a teat canal 20. The inner barrel 2 comprisesa distal end 74 having an outlet 75 and the barrier comprises a valve 70which is received in the outlet 75. The valve 70 is normally closed(FIGS. 14(a), (b)) during delivery of the first component from the outerbarrel 3. An activator 71 projects upwardly from the lower wall of theouter barrel 3. In use, when all of the first component has beendelivered and the inner barrel 2 is in the configuration of FIG. 14(c)the valve 70 is released by engagement with the activator 71 and theseal component 9 in the inner barrel 2 is allowed to pass through sidepassageways 76 in valve through the outlet 75 and into the injectornozzle 4.

The inner wall of the inner barrel 2 is formed for engagement with theplunger 6 and comprises a locking ring 173 between the proximal anddistal ends thereof. The inner barrel 2 comprises a distal portion 178and a proximal portion 179, the distal portion 178 having an internaldiameter less than the internal diameter of the proximal portion 179.The plunger 6 comprises a seal 77 which passes over the locking ring 173of the inner barrel on assembly and the plunger 6 is thus sealinglyengaged with the inner barrel 2.

The inner barrel 2 further comprises an external seal 72 for engagementwith the internal wall of outer barrel 3. The external seal 72 may forexample comprise an integrally formed seal or an o-ring housed in arecess 172 in the external side wall of the inner barrel 2. The externalseal 72 is located near the distal end 74 of the inner barrel.

The internal wall of the outer barrel 3 is formed for engagement withthe inner barrel 2 and comprises a locking ring 73 between the proximaland distal ends thereof for engagement with the external seal 72 of theinner barrel 2 The outer barrel 3 comprises a distal portion 78 and aproximal portion 79. The distal portion 78 having an internal diameterless than the internal diameter of the proximal portion 79. The externalseal 72 passes over locking ring 73 of the outer barrel 3 on assemblyand sealingly engages the outer barrel. The antimicrobial or anti-inflammatory formulation 10 is thus prevented from passing between thebarrels as the plunger 6 is depressed.

The valve 70 comprises a plurality of channels 76 which are exposed whenthe valve 70 is released to allow the seal component to pass out throughthe valve. Thus upon releasing of the valve the channels 76 which definea passageway for the seal component are opened.

The activator 71 defines a substantially cylindrical form defining apassageway and corresponds in form to the outlet 75 enabling it to bereceived in a portion of the outlet. The activator 71 is a close fitwith the outlet 75.

In use the inner barrel 2 is pushed through the outer barrel 3 by theplunger 6 to expel the antimicrobial 10 (FIG. 14(a)). The outside of theinner barrel 2 has the geometry of the plunger 6 so that the innerbarrel 2 itself acts as a plunger. When the antimicrobial 10 has beenexpelled (FIG. 14(b)) the plunger 6 on the inner barrel 2 is furtherdepressed to expel the seal 9 from the inner barrel 2. The valve 70 isreleased by engagement of the inner barrel with the activator 71 and theseal component 9 in the inner barrel 2 is allowed to pass through thevalve passageways into the injector nozzle 4 and is expelled into theteat canal (FIG. 14(c)).

Referring to FIGS. 14 to 16, and in particular FIGS. 16(b) and (c) theoperation of the valve is described in more details.

When closed the valve 70 which is a close fit with the outlet 75 restsin the outlet and prevents any mixing of the components in the outer andinner barrels (FIGS. 14(b) and 16(b)).

When the activator 71 is received in the outlet 75 (FIGS. 14(c) and16(c)) the valve is released and the passageways 76 in the valve areopened to enable the seal component to pass into the valve passageways76 through the passageway defined by the activator 71 and into theinjector nozzle 4.

The engagement of the activator 71 with the outlet of the inner barrel 2provides for alignment of the respective passageways 76 of the valve andthe activator before the valve is released and the seal component isallowed to pass from the inner barrel. The respective passageways 76 ofthe valve and activator provide a closed and isolated pathway for theseal component to pass from the inner barrel 2 directly into theinjector nozzle 4.

One advantage of a valve type barrier of this embodiment is that thereis not risk of any part of the barrier becoming mobile. The barrier isretained with the injector.

Referring to FIGS. 17 to 18 there is illustrated an injector device 81of an alternative embodiment of the invention (which is similar to theinjector of FIGS. 1 to 16 and like parts are assigned the same referencenumerals). The injector device 81 comprises a barrel 3, an outlet nozzle4 and a plunger 6. Two incompatible components 9 and 10 are placedwithin the barrel 3 of the injector device 81. The two components suchas an antimicrobial 10 and a seal 9 are separated from one another by abarrier/membrane. The antimicrobial 10 is placed in the barrel 3 and aseal 9 is placed in a receptacle 86 such as a bag which is defined by anouter membrane 87 which provides the harrier.

The receptacle 86 may comprise a capsule into which the seal is filledon manufacture. The capsule may then be readily dropped into the barrel3 of the injector before a plunger 6 is inserted.

When the nozzle 4 of the device 81 is inserted into a teat canal 16 auser depresses the plunger 6 to effect delivery of the antimicrobial 10from the injector device into the teat canal (FIG. 17(a)). After theantimicrobial 10 is expelled from the injector device further pressureapplied to the plunger results in puncturing or bursting of thereceptacle 86 allowing egress of the seal 9 which is delivered into theteat canal (FIG. 17(b)). FIG. 17(d) shows the position of a sealformulation 9 and antimicrobial formulation 8 on delivery into the teatof a non-human animal.

The injector device may comprise rupturing means such as sharp teeth 88at the distal end of the barrel 3 to assist in puncturing or burstingthe receptacle 86.

It will be appreciated that for ease of manufacture and use, thereceptacle 86 may be attached to the plunger 6. In this case thereceptacle is unable to come into contact with the rupturing deviceuntil substantially all of the first component has been expelled fromthe device.

When delivering a seal 9 and antimicrobial or anti-inflammatoryformulation 10 into the teat canal of a non-human animal the injectordevice is typically positioned vertically below the teat with thedelivery nozzle uppermost. The seal formulation 9 has a much higherspecific gravity than the antimicrobial or anti-inflammatory formulation10 and therefore the receptacle containing the seal formulation remainsat the lower end of the barrel 3 containing the antimicrobial oranti-inflammatory formulation during the delivery of the antimicrobialor anti-inflammatory formulation into the teat. In this case thereceptacle comes into contact with the rupturing device only whensubstantially all of the antimicrobial or anti-inflammatory formulationhas been delivered into the teat.

Referring to FIGS. 19 and 20 there is illustrated another injectordevice 90 of the invention. The injector device 90 comprises an innerbarrel 92 and an outer barrel 93. The outer barrel 93 has a nozzle 94.The inner barrel 92 comprises a breakable/burstable barrier or membraneat its distal end and a plunger 98 at its proximal end. Antimicrobial 10is contained within the outer barrel 93. In use, the nozzle 94 isinserted into a teat canal 16. The inner barrel 92 is pushed through theouter barrel 93 to expel the antimicrobial (FIG. 20(b)). This proceduremay be facilitated by a flange 97 around the proximal end of the innerbarrel 92 and a flange 99 around the proximal end of the outer barrel93. When the antimicrobial 10 has been expelled (FIG. 20(c)) the plunger98 on the inner barrel 92 is depressed to expel the seal 9 from theinner barrel 91. The pressure of the plunger 98 is sufficient to burstor rupture the barrier/membrane 96 on the inner barrel 92 allowing theseal 9 to be expelled from the injector device through the nozzle 94 andinto the teat canal (FIG. 20(c)). Alternatively rupturing means such assharp teeth situated within the outer barrel 93 at its aperture into thenozzle, ruptures the barrier/membrane 96.

A seal 96 may be provided at the front end of the inner injector barrel92 to provide a positive seal. The inner injector may be moulded with aweak burstable barrier/membrane 95 across the outlet aperture.

It will be appreciated that the seal portion of the formulation may bemanufactured in one facility and subsequently combined with theanti-bacterial portion of the formulation at a later stage, in the sameor another facility.

The invention is not limited to the embodiments hereinbefore describedwhich may be varied in detail.

1-63. (canceled)
 64. An injector device for delivery of components intoa teat canal of a non-human animal, to treat, prevent or suppressinfection with a mastitis causing micro-organism, said devicecomprising: a barrel containing a first component, an outlet nozzle forinsertion into the teat canal, at one end of the barrel, an internalreceptacle containing a second component, a barrier for separating thefirst component and the second component, and a delivery means fordelivery of the first component from the barrel and sequential deliveryof the second component from the internal receptacle through the outletnozzle without substantial mixing of the first and second components;wherein the barrier is releasable for delivery of the second component;the internal receptacle comprises an inner barrel located within anouter barrel defined by the barrel of the injector; the inner barreldefines a plunger for the outer barrel; the delivery means comprises theinner barrel and a plunger for the inner barrel; the first componentcomprises an antimicrobial formulation; and the second componentcomprises a seal formulation.
 65. An injector device as claimed in claim64, wherein the barrier is normally closed.
 66. An injector device asclaimed in claim 64, wherein the barrier is defined by at least aportion of the internal receptacle.
 67. An injector device as claimed inclaim 64, wherein the barrier comprises one or more passageways.
 68. Aninjector device as claimed in claim 67, wherein the one or morepassageways are opened when the barrier is released for delivery of thesecond component through said one or more passageways.
 69. An injectordevice as claimed in claim 64, wherein the device comprises an activatorfor releasing the barrier.
 70. An injector as claimed in claim 69,wherein the activator comprises at least one projecting member.
 71. Aninjector as claimed in claim 64, wherein the inner barrel comprises anexternal seal for engagement with the outer barrel on assembly.
 72. Aninjector as claimed in claim 64, wherein the inner barrel comprises alocking ring for engagement with the plunger for the inner barrel. 73.An injector device as claimed in claim 69, wherein the activatorcomprises a rupturing means for at least partially releasing thebarrier.
 74. An injector device as claimed in claim 64, wherein the sealformulation comprises between 50% and 75% by weight of bismuthsub-nitrate in a gel base.
 75. An injector device as claimed in claim64, wherein the antimicrobial is selected from any one or more ofbetalactam antibiotics, polymyxins, glycopeptides, aminoglycosides,lincosamides, macrolides, pleuromutilins, “fenicols” such aschloramphenicol and florfenicol, tetracylcines, sulphonamides andpotentiated sulphonamides such as mixtures of trimethoprim and one ormore sulphonamide, quinolones and fluoroquinolones, ionophores,courmarins such as novobiocin, natural or synthetic peptides,aminoglycosides, antimicrobial peptides or antimicrobials, lantibiotics,or other products of bacteria and other micro-organisms.
 76. An injectordevice as claimed in claim 75, wherein the betalactam is selected fromany one or more of penicillin, modified penicillin such as cloxacillin,amoxicillin, ampicillin, cephalosporins or beta lactam antibioticspotentiated by beta lactamase inhibitors such as clavulanic acid.
 77. Amethod for treating, preventing or suppressing mastitis or an infectionwith a mastitis causing micro-organism, said method comprising the stepsof sequentially delivering an antimicrobial formulation and a sealformulation from a single delivery device into a teat canal of anon-human animal, wherein the antimicrobial formulation and the sealformulation are delivered into the teat canal without substantial mixingof the formulations prior to delivery into the teat canal.
 78. A methodas claimed in claim 77, wherein the device is an injector device asclaimed in claim
 1. 79. A method as claimed in claim 77, wherein theseal formulation comprises between 50% and 75% by weight of bismuthsub-nitrate in a gel base.
 80. A method as claimed in claim 77, whereinthe antimicrobial is selected from any one or more of betalactamantibiotics, polymixins, glycopeptides, aminoglycosides, lincosamides,macrolides, pleuromutilins, “fenicols” such as chloramphenicol andflorfenicol, tetracylcines, sulphonamides and potentiated sulphonamidessuch as mixtures of trimethoprim and one or more sulphonamide,quinolones and fluoroquinolones, ionophores, courmarins such asnovobiocin, natural or synthetic peptides, aminoglycosides,antimicrobial peptides or antimicrobials, lantibiotics, or otherproducts of bacteria and other micro-organisms.
 81. A method as claimedin claim 80, wherein the betalactam is selected from any one or more ofpenicillin, modified penicillin such as cloxacillin, amoxicillin,ampicillin, cephalosporins or beta lactam antibiotics potentiated bybeta lactamase inhibitors such as clavulanic acid.